Journal of Herbs, Spices & Medicinal Plants

ISSN: 1049-6475 (Print) 1540-3580 (Online) Journal homepage: http://www.tandfonline.com/loi/whsm20

A Review on Medicinal Properties of Saffron

toward Major Diseases

Saiful Izwan Abd Razak, Mohd Syahir Anwar Hamzah, Foong Choi Yee,
Mohammed Rafiq Abdul Kadir & Nadirul Hasraf Mat Nayan

To cite this article: Saiful Izwan Abd Razak, Mohd Syahir Anwar Hamzah, Foong Choi Yee,
Mohammed Rafiq Abdul Kadir & Nadirul Hasraf Mat Nayan (2017): A Review on Medicinal
Properties of Saffron toward Major Diseases, Journal of Herbs, Spices & Medicinal Plants, DOI:
10.1080/10496475.2016.1272522

To link to this article: http://dx.doi.org/10.1080/10496475.2016.1272522

Published online: 17 Feb 2017.

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JOURNAL OF HERBS, SPICES & MEDICINAL PLANTS
http://dx.doi.org/10.1080/10496475.2016.1272522

A Review on Medicinal Properties of Saffron toward Major

Diseases
Saiful Izwan Abd Razaka,b, Mohd Syahir Anwar Hamzahb, Foong Choi Yeeb,
Mohammed Rafiq Abdul Kadirb, and Nadirul Hasraf Mat Nayanc
a
IJN-UTM Cardiovascular Engineering Centre, Universiti Teknologi Malaysia, Skudai, Johor, Malaysia;
b
Faculty of Biosciences and Medical Engineering, Universiti Teknologi Malaysia, Skudai, Johor, Malaysia;
c
Faculty of Engineering Technology, Universiti Tun Hussein Onn Malaysia, Batu Pahat, Johor, Malaysia

ABSTRACT ARTICLE HISTORY

The stigma of Crocus sativus, known as saffron, is one of the Received 16 June 2016
most expensive spices in the world. The bioactive components
KEYWORDS
in saffron, picrocrocin, crocin, and safranal, have demonstrated Crocus sativus; herbal
a wide range of uses and capabilities in the medical field. This medicine; diabetes mellitus;
review is focused on the potential therapeutic applications of cardiovascular disease;
saffron on diabetes mellitus (DM), antitumor, anticancer, anti- antidepressant; cancer;
depressant, Alzheimer’s disease (AD), cardiovascular disease erectile dysfunction;
(CVD), erectile dysfunction and antibacterial effects. antibacterial

Introduction
Crocus sativus (Iridaceae) (Figure 1) flowers only during autumn and is
dormant during summer. Its stigma, named saffron, derived from the
Arabic name azaferan, is one of the most expensive spices in the world.
Physiologically, C. sativus has lilac to mauve-colored tepals (51). The stigma
is bright red in color and can grow as long as 25–30 mm. It is propagated
vegetatively, as the flowers are sterile.
The cultivation of saffron is spread from the eastern Mediterranean region
to Europe as well as to Asia. Iran is the main producer of saffron in the
world, with an annual production of ~230 tons, accounting for ~93.7% of the
world total production in 2005 (51). High or low temperatures of the
summer or winter do not affect the plant growth, however, extreme low
temperature or extreme humid environment does not promote growth of this
plant.
Flowering usually lasts about four or five weeks, and the only way to
harvest the crop is by hand picking, which is time-consuming. Each flower
has only three stigmas, and to produce 1 kg of saffron spice, about 63 kg of
flowers are needed (51). It takes ~14–55 min to pick 1,000 flowers and

CONTACT Saiful Izwan Abd Razak saifulizwan@utm.my IJN-UTM Cardiovascular Engineering Centre,
Universiti Teknologi Malaysia, 81310 Skudai, Johor, Malaysia.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/whsm.
© 2017 Taylor & Francis Group, LLC
2 S. I. ABD RAZAK ET AL.

Figure 1. Crocus sativus flower and the stigma.

another 100–130 min to remove the stigmas for drying, thus overall the
whole process takes about 370–470 hours to produce 1 kg of dried saffron.
With regard to their medicinal usage, many scientific articles have been
published documenting antioxidant properties and treatment of cancer and
cardiovascular disease. Reviews on these matters also have been given
throughout the literatures (7, 11, 27). The antioxidant property is a major
contributor that helps to prevent or reduce diseases (35).

Saffron farming
Warm subtropical climate and well-drained sandy soils are the most suitable
and preferable for saffron planting. Overly humid soils are not suitable for
the plant growth because water is unable to flow easily. Therefore, siliceous,
argillaceous-ferruginous, and chalky dry soils are preferred. Best soils for
saffron farming are calcium containing soils, because the calcium will help to
break down or decompose organic compounds easily. A solid underground
corm of the saffron plant is terminated at its adventitious roots. The corm
reproduces annually, and the new young corm replaces the dead or older
ones. Plowing or preparation of soil for the saffron should be done by hand
digging to prevent the corms from damage. The corm production is affected
by the planting depth.
Saffron plants only bloom for about 15 d, and the flowers are picked
manually every morning before the sun gets too hot, cleaned, and the style
and stigmas are separated from the perianth on the same day, as the flower
will wilt the next day and the separation of stigmas becomes very difficult. A
mechanical saffron flower harvesting system has been developed to harvest
the flower without separating the saffron flower from the leaves, which can
simplify the mechanical detachment of the flower and thus prevent the fragile
stem bends and breaks. This can ensure that a perfect flower can be pick up
by the workers (6).
 JOURNAL OF HERBS, SPICES & MEDICINAL PLANTS 3

The harvested stigmas are dehydrated and preserved as saffron. Stigmas

lose about 80% of their weight during the drying process, and the physical,
biochemical, and chemical properties change during this process. A moisture
content of <12% is needed to maintain and preserve the quality of product
for a longer period (ISO 3632, 29).
There are two dehydration methods that vary in terms of temperature: one
is done at room temperature directly under sun or in air-ventilated condi-
tions, and the second method is by drying at higher temperatures using hot
air or any other heating source. India, Morocco, and Iran carry out the
drying process through the first method, while in India the stigmas are
dried under the sun for 3–5 d until the moisture content is reduced to
8–10% (33). In Morocco, the stigmas are spread on a cloth in a very thin
layer and dried under the sun for a few hours or in shade for 7–10 d.
In Italy, stigmas are spread on a sieve and placed above live oak-wood
charcoal at a distance of ~20 cm above the heat source; during the dehydra-
tion process, stigmas are turned to ensure that all the stigmas are dried
evenly. When the stigmas do not crumble and still contain a certain amount
of elasticity when pressed between the fingers, the dehydration is stopped at
~5–20%. Drying in Greece starts with spreading the fresh stigmas and part of
the stamens on shallow-layer trays with a silk cloth on the bottom. During
the first hours of the dehydration process, the room temperature is main-
tained at 20°C and then it is increased to 35–45°C. The relative humidity is
maintained at ~50%. Dehydration is stopped when the moisture is reduced to
~10–11%, and this takes about 12 h (44).
The drying process in Spain is called toasting. First, stigmas are spread on
a sieve with a silk bottom. Then the sieve is placed over a heating source,
which can be a gas cooker, live vine shoot charcoal, or an electric coil. The
process is stopped when 85–95% of the moisture has been lost (3).
Brightest color was obtained at higher temperature of 83ºC and lower
heating times of 28 min. This was due to the more porous sample obtained at
high temperature compared to that of the dehydrated sample at room
temperature (10). Mild condition (55ºC) during the dehydration produced
good saffron coloring, and more volatile compounds, mainly safranal, were
generated during the dehydration procedure at 55ºC (16).

Traditional use of saffron

Saffron has been used in European cuisine since antiquity to color and flavor
foods. In addition, it is one of the important and traditional ingredients in
German saffron cake, called Gugelhupf. Some dairy products also include
saffron for flavor and color. Ancient Romans believed that saffron had the
ability to prevent hangovers when used for steeping their wine. It also has
sedative, antispasmodic, expectorant, as well as aphrodisiac properties.
4 S. I. ABD RAZAK ET AL.

Higher dosage of saffron may to be toxic, having been used as an abortifa-

cient formerly, and fatal cases have been reported when saffron was used as
an abortifacient. Excessive dosage can lead to temporary paralysis.
Furthermore, saffron corms have a huge effect on young animals, and it
can be used as a narcotic drug when overdosed (39).

Chemical composition of saffron

Saffron is composed of water, nitrogenous matter, sugars, soluble extracts,
volatile oil, and fibers. Saffron is rich in vitamins riboflavin (56–138 μg.g–1)
and thiamine (0.7–4 μg.g–1) (7). The bitter taste of saffron originates from its
picrocrocin (β-D-glucosida of hydroxysafranal). The cleavage of carotenoid
zeaxanthin will produce picrocrocin and crocin as well as safranal [Figure 2
(47)]. It is a glycoside resulting from the cracking of acid and alkali into a
glucose molecule and an aglycon. This aglycon easily undergoes hydrolysis
and turns into volatile safranal. The increase in temperature while drying
converts the picrocrocin into safranal. Zeaxanthin, reddish in color, is one of
the carotenoids found naturally in retina.

Figure 2. Cleavage of zeaxanthin produces secondary metabolites (47).

 JOURNAL OF HERBS, SPICES & MEDICINAL PLANTS 5

The aroma of saffron corresponds to safranal, and it is ~70% of the volatile

fraction. The fresh stigma has no smell because the picrocrocin has not
hydrolyzed. The absorbance of picrocrocin at 257 nm is inflated due to the
interference with the crocetin ester as compared with the high-performance
liquid chromatography (HPLC) data corroborated with the Fourier trans-
form infrared analysis (17). The sharp smell of saffron appears during the
drying and storage stage of saffron. The drying can cause enzymatic or
thermal dissociation. The maximum UV absorption of safranal is 330 nm.
Its aroma profile depends on its geographical origin, as the producing
countries use different postharvesting methods; the difference lies primarily
in the method of dehydration. It is important to identify the origin and
mechanism by which the volatile compounds are generated (11). Crocin gives
color to saffron; it is a crocetindigentiobiose ester (C20H24O4) with a beta-
shaped glycosidic bond. It is able to undergo hydrolysis by breaking the beta-
shaped glycosidic bond. Crocin is a unique water-soluble carotenoid in
nature. It is a water-soluble crocetin that can dissolve in water easily and
produce an orange-red solution, with maximum UV absorption of 440 nm,
the highest and most easily detachable among the constituents. The identi-
fication of crocetin esters is done by using a liquid chromatography-electro-
spray ionization-mass spectrometry method (9).
The chemical composition of saffron is determined by HPLC with diode
array detection using aqueous extract as per ISO 3632. The quality of saffron
(crocetin esters, picrocrocin, and safranal) can be determined using this
method as suggested in ISO 3632 (21). No qualitative differences in relation
to the flavonoid fraction were observed when saffron samples from different
geographical origins were analyzed. This could be due to the poor genetic
variability between cultivars. Difference in flavonoid profile was noted due to
postharvesting methods, and and the highest flavonoid was reported for
Spanish saffron (12).

Pharmacological properties and potential therapeutic application of

saffron
Saffron and its active components picrocrocin, safranal, and crocin have been
explored for a large number of possible medicinal usages. The pharmacolo-
gical properties of active components of saffron are due to their unique
chemical structure.

Diabetes mellitus
Diabetes mellitus (DM) is a metabolic disorder that occurs when the pan-
creas loses its ability to produce adequate insulin for the body or in some
cases the body fails to use the insulin efficiently. Uncontrolled DM may lead
6 S. I. ABD RAZAK ET AL.

to high blood sugar level or hyperglycemia, which in the long term can cause
severe damage to the body’s systems. The World Health Organization
(WHO) reports that the number of people with DM has risen from 108
million in 1980 to 422 million in 2014, and is expecting it to become the
seventh-leading cause of death in 2030, leading to heart attacks, stroke, liver
failure, and kidney failure. There are three types of DM (59): Type 1 (T1DM),
deficient in the production of insulin by the body due to pancreatic β-cell
failure, which requires daily administration of insulin and is known as
insulin-dependent, juvenile, or childhood-onset; Type 2 (T2DM), non-insu-
lin-dependent or adult-onset, characterized by a progressive decline in β-cell
function and chronic insulin resistance; and gestational DM, which occurs
when women develop insulin resistance during pregnancy.
Factors that contribute to DM include unplanned diet that leads to obesity.
Higher body mass index (BMI) is associated with poorer metabolic control,
increasing insulin resistance, greater hemoglobin A1c (HbA1c), and
increased frequency of severe hypoglycemia. There are also reports of other
factors such as demographic characteristics (i.e., age, sex, ethnicity), family
history of diabetes, smoking, sedentary behavior, psychological stress, dysli-
pidemia, and rarely, social deprivation (18). The relation of systemic inflam-
mation to diabetes for T1DM remains ill-defined, but for T2DM it has
emerged as a prominent factor. Although the relation for T1DM is still
unclear, there is evidence that can be accepted to relate the chronic inflam-
mation of pancreatic islets as central to T1DM.
After a patient is diagnosed with diabetes, the treatments are based on the
type of diabetes and the special condition of the patient. Tracking metabolic
control from childhood until adulthood enable the prevention of T1DM, as
the alteration of growth hormone/insulinlike growth factor-1 axis and
abnormalities of ovarian function lead to insulin resistance. In additon,
metabolic control is related to glycated HbA1c and micro-/macrovascular
complication that correlates with the risk of coronary heart disease (25).
In most cases, the use of insulin has been implemented, but after blood
glucose is controlled, it can be consumed by the patient where the insulin
may be derived from biological sources such as cow. However, in T2DM
cases there is a negative appraisal of insulin treatment known as “psycholo-
gical insulin resistance” that leads to the delay of insulin initiation (26).
Blood glucose control is the main defence in this disorder before proceeding
to other treatment. Sulfonylureas are the oldest drugs that have been used,
and in addition there are six classes of oral glucose-lowering drugs: bigua-
nides (e.g., metformin), sulfonylureas (e.g., glimepiride), meglitinides (e.g.,
repaglinide), thiazolidinediones (e.g., pioglitazone), dipeptidyl peptidase IV
inhibitors, and alpha glucosidase inhibitors (e.g, acarbose) (59). There are
also reports on the use of metal drugs in several treatments such as for
diabetes, cancer, rheumatoid arthritis, and inflammatory and cardiovascular
 JOURNAL OF HERBS, SPICES & MEDICINAL PLANTS 7

disease. In diabetic cases, metallopharmaceuticals based on vanadium have

potential in glycemic control, as it is hypoglycemic. Other than that, meta-
formin and its derivatives such as metforminium decavanadate (MetfDeca)
have better intracellular biochemical behavior and in recovering lipid and
carbohydrate levels. Metaformin may have some side effects such as risk of
lactic acidosis, vitamin B12 deficiency, gastrointestinal side effects, and
chronic kidney disease (57).
There are reports on Trigonella foenum-graecum (funegreek) that
demonstrated antidiabetic properties by altering levels of malondialdehyde
(MDA), 4-hydroxynonanal (4HNE), superoxide dismutase (SOD), glu-
tathione peroxidase (GPx), and catalase (CAT) in tissues (53).
Bougainvillea spectabilis leaves reduced hyperglycemia and hyperlipidemia
level along with antioxidant activity which make it a potential candidate
for DM treatment (13).
Saffron has been studied as a potential candidate drug for DM. The major
active constituents that give antidiabetic response are crocin, crocetin, and
saffranal which display insulin-sensitizing effects that will not have any
significant effect on blood serum glutamic oxaloacetic transaminase
(SGOT), serum glutamic-pyruvic transaminase (SGPT), and creatinine levels
(32). The main hypotheses for the modes of saffron on its inhibitory effect on
free-radical chain reactions are its capability to modulate antioxidant gene
expression and upregulate mitochondrial antioxidant genes, leading to lower
mitochondrial oxygen radical generation. Results have shown that saffron
stimulated the glucose uptake in skeletal muscle cells by activating 5′-AMP-
activated protein kinase (AMPK) as well as improving the insulin sensitivity
in glucose metabolism, preventing excess glucose accumulation in blood.
Studies also report oral administration of saffron increasing serum insulin
levels and reducing blood glucose levels, as well as improving the lipid
profile, and liver and kidney function, of diabetic rats. Other than that,
saffron is reported to increase glutathione content (GSH) and superoxide
dismutase (SOD) that help in glucose reduction as well as helping in regen-
eration of damaged pancreas. Saffron also has antioxidant properties that can
reduce not only hyperglycemia but also oxidative stress, which may give
benefit toward treatment of diabetic encephalopathy (50).

Antitumor and anticancer

Cancer develops when a cell grows abnormally, which means it divides
without stopping and in some cases leads to formation of tumors. There
are several type of cancers, depending on the origin: leukemia (blood),
carcinoma (epithelial cells), sarcoma (bone and soft tissues: muscle, fat,
blood and lymph vessels, fibrous tissues), lymphoma (lymphocytes: T or B
cells), multiple myeloma (plasma cells), melanoma (cells that become
8 S. I. ABD RAZAK ET AL.

melanocytes), brain and spinal cord tumors, germ-cell tumors, neuronendo-

crine tumors, and carcinoid tumors.
Cancer can be caused by multiple situations in which some may be
infected by cancer-causing substances (carcinogens), genetics, the immune
system, age, and human daily routine, which is rarely observed.
Psychoneuroimmunology is study focused on psychological aspects of
humans toward cancer risk, especially stress and depression effects from
daily routine. Chronic stress and depression can activate the hypothalamic-
pituitary-adrenal (HPA) axis, impairing immune response and enhancing
development and progression of some cancers. The activation may be due
to production of glucocorticoid hormones and catecholamines that interfere
with the function of NF-kB, which regulates the activity of cytokine-produ-
cing immune cells and reduces the number of natural killer cell activities,
causing somatic mutations and genomic instability (58).
Cancer treatment depends on the diagnosis and may include surgery,
radiation, chemotherapy, or immunotherapy. Scientists are interested in
combining chemotherapy with immunotherapeutic agents as a new potential
approach for cancer treatment (58). Tumor vessels have permeability and
retention effect due to absence of encapsulated seals compared to healthy
human blood vessels, thus making development of new drugs or therapeutic
agents more challenging (20).
Flavonoids are one of the chemotherapeutic agents that give positive
immune effect via antioxidant, anti-inflammatory, and anticyclooxygenase
activities such as epigallocatechin-3-gallate (EGCG) and apigenin.
Epigallocatechin-3-gallate (EGCG), found in green tea, in combination with
DNA vaccine was effective in inhibiting bulky tumor growth while replacing
it with apigenin could improve multimodality treatment against progressive
tumors (14). Studies also showed an excellent antitumor effect and long-term
survival using cisplatin with DNA vaccines encoding calreticulin (CRT)
linked to human papillomavirus type 16 E7 antigen (CRT/E7) in a preclinical
model. Cisplatin is a type of chemotherapeutic agent commonly used in
treating cancers such as ovarian, breast, and cervical (58).
Several isolated compounds such as flavone, carotenoids, isothiocyanates,
polyphenols coumarins, α-angelica, gingerols, curcumin, and other polyphe-
nols from plants (soy, broccoli, green tea, turmeric, tomato, saffron, garlic,
and black cumin) have been reported to inhibit the growth and progression
of chemically induced tumors. Saffron can be used as an agent in chemo
preventive therapy. The ability of saffron to inhibit synthesis of DNA and
RNA, but not protein, remove free radicals, involve the processes of conver-
sion of carotenoids to retinoids, and promote the interaction mediated via
lectins confirmed that saffron has antitumor and anticancer properties (23).
It is suggested that crocin is the major antitumor ingredient in saffron.
Studies show that mice treated with crocin were 100% tumor-free, while
 JOURNAL OF HERBS, SPICES & MEDICINAL PLANTS 9

DNA vaccine alone led to approximately 66.7% and 33.3% treated with DNA
+crocin. Furthermore, safranal also showed the capability to inhibit HeLa
cell-line growth, profileration of MDA-MB-231 and MCF-7 cell lines, and
suppress some biochemical markers of toxicity by diazinon. Crocetin has
potential as an antitumor agent by inhibiting nucleic acid synthesis, enhan-
cing the antioxidative system, inducing apoptosis, and hindering growth
factor signaling pathways (23). Caspases and bax protein in saffron can act
as a chemotherapeutic agent as it can reduce cell viability of MCF-7 cells (a
common cell used for breast cancer study) and apopotic cell death treated
with saffron extract (24). Saffron can be used in combination with liposome
to improve its antitumor effect, as liposome serving as a host can rapidly
enter tumor sites from blood.

Treatment for Alzheimer’s disease

Alzheimer’s disease (AD) is the most common disease among the elderly.
AD, a dementia disease, can cause gradual deterioration of intellectual func-
tions leading to the loss of ability to complete routine daily activities; the
personality and behavior of patients changes as well. AD has affected 27
million people worldwide; the number is expected to increase and reach 86
million by 2050 (19).
AD is the most common neurodegenerative disorder that may be inherited
directly from family. Age is the major factor, in that ~40–50% of people 85
years old face AD. Another risk factor may be an apolipoprotein E (APOE)
genotype that exists in the family history, which is capable of shifting the age
at onset to an earlier time point. The factor that causes AD is in the cerebral
cortex; there are numerous amyloid plaques present, the main component of
the plaques is amyloid β (Aβ), and the neuronal damage may be due to
deposition of Aβ (2, 13). There is also evidence of genomic risk contributing
as a factor for AD for variation in CLU (encoding clusterin), PICALM
(encoding the phosphatidylino-sitol binding clathrin assembly protein), and
CR1 (encoding complement component receptor 1).
The treatments or biological action needed may differ with the types of
AD itself, depending on the onset time, which are early-onset AD (EOAD:
before the age of 60 years) and late-onset AD (LOAD: after the age of 60
years). The most well established biomarkers for presymptomatic detection
of this disease can be divided into two major groups depending on function-
ality: (1) measures of brain Aβ deposition and (2) measures of neuronal
injury and degeneration. Cerebrospinal fluid (CSF) is a valid source as an AD
biomarker, as well as positron emission tomography (PET) amyloid imaging,
which is categorized as the first group (19, 30). The second group is more
focused on CSF tau (total and phosphorylated tau), fluorodeoxyglucose
(FDG) PET, and structural magnetic resonance imaging (MRI). Blood
10 S. I. ABD RAZAK ET AL.

analysis is advantageous because it is simple and less invasive, and an 18-

biomarker panel has been identified from a group of 120 signaling proteins
that can detect AD symptoms (30).
There are several methods used to treat AD, from dietary implementation
to chemical and biological means, but there is no effective treatment for this
disease. Indeed, there are two limitations that need to be considered to
develop treatment for AD: (1) the use of drugs that are highly specific
because they fundamentally may cause harm than good; and (2) delivery of
drugs to the brain is more difficult than to other organs. As the neuronal
damage may be related to oxidative action by free-radical species, an anti-
oxidant-rich diet may able to reduce the risk of AD. Common antioxidants
used are vitamin C, vitamin E, α-lipoic acid (ALA), and co-enzyme Q (CoQ),
but the problem with antioxidants is in determining the right dosage.
Vitamin C with the combination of vitamin E is able to reduce oxidative
damage and improve performance of spatial memory. Treatments with
vitamin E only will attenuate plaque formation if the treatment is started
before amyloid deposits are present. Messing (2016) reported that bacter-
iophage M13 infects Escherichia coli (E. coli) and has been used to reverse the
formation of plaques derived from amyloid-like structures in the brain and
itself could reverse the aggregation of misfolded proteins (42).
Current drugs used to treat AD are cholinesterese inhibitors (donepezil,
rivastigmine, and galantamine) and N-methyl-D-aspartate receptor antago-
nists (memantine). There are also reports combining these two types of drug
to enhance the therapeutic benefit, but there are a lack of reports that show
improved cognition, function, and behavior of treated patients (46). Ferulic
acid (4-hydroxy-3-mthoxy cinnamic acid, FA) has anti-inflammatory and
antioxidant effect plus the capability to inhibit Aβ fibril aggregation, prevent
Aβ-mediated toxicity, and improve cognitive ability. Histone deacetylase 6
inhibitor (ACY-738) modulated tubulin acetylation in amyloid protein/pre-
senilin 1, but it has seen limited progress due to low blood–brain barrier
penetration (38).
Saffron has been reported to improve learning and memory properties,
have a genoprotective effect, and protect from genotoxins-induced oxidative
stress due to a wide range of bioactives that are present. It is a great source of
carotenoids such as crocins, that is, mono- and diglycosides of crocetin
(CRT), as well as a source of acetylcholinesterase inhibitors for AD treat-
ment. Studies also revealed that saffron counteracted age-related memory
impartments, improved cerebral antioxidant markers, decreased acetylcholi-
nesterase (Ache) activity, and has effect against scopolamine-induced recog-
nition deficits in adult mice and rats (55). Crocin enhanced learning and
memory functions as well as had preventive effect on long-term potentiation
(LTP) which is blocked by ethanol in vivo. Long-term potentiation (LTP) is a
form of activity-dependent synaptic plasticity and is believed to be a cellular
 JOURNAL OF HERBS, SPICES & MEDICINAL PLANTS 11

basis of learning and memory in the hippocampus. In addition, crocin can be

used in the ethanol inbibition of NMDA receptor activities compared to
picrocrocin (1). Saffron eliminated the accumulation of amyloid β in the
human brain due to the protective effect of crocin, enhancing the stability of
proteins.

Cardiovascular disease
Cardiovascular disease (CVD) is a generic term that describes heart and
blood vessels disease that may result from blood flow to the heart being
reduced as the result of a blood clot (thrombosis) or buildup of fat plaque
in walls of arteries (atherosclerosis). There are several types of CVD (55):
(1) heart attack, due to blockage of blood flow to the heart by blood clot,
also known as coronary heart disease that may cause angina (chest pain);
(2) stroke, a medical condition where the brain is damaged or death
occurs due to cut-off blood supply to the brain due to blockage, which
known as ischemic stroke; (3) heart failure, also known as congestive heart
failure, which means the heart is not pumping as well as it should,
resulting from the insufficient oxygen-enriched blood supply to all parts
of body; (4) arrhythmia, an abnormal rhythm of the heart due to electrical
properties of the heart, where the heart beat may be too slow, too fast, or
irregular; (5) heart valve problems, where the valve may function abnor-
mally, such as in stenosis, where the valve may not open enough for blood
flow, regurgitation, where valve does not close properly, causing backward
flow of blood, and mitral valve prolapse; (6) others, referring to blockage
of certain main blood vessels related to heart function, such as peripheral
arterial disease and aortic disease. There are several factors that lead to
CVD: high blood pressure (hypertension), smoking, high blood choles-
terol, diabetes mellitus (DM), lack of exercise, obesity, family history, and
ethnicity.
Diet that is recommended for a healthy heart is a low-fat, high-fiber diet
and unsaturated-fat food such as oily fish, avocados, rapeseed oil, and olive
oil (55). Phytotherapy is broadly defined as the use of natural therapeutic
agents derived from plants or crude herbal drugs. Ligusticum chuanxiong
Hort, Dalbergia odorifera T. Chen, and Corydalis yanhusuo WT Wang are
representatives of Chinese herbs in CVD treatment in which have been
identified 54 proteins of 64 bioactive ingredients closely associated with
CVD (34). Consuming food rich in antioxidants such as blueberries, black
plums, and prunes that contain vitamin C, carotenoids, and vitamin E may
prevent atherosclerosis by blocking the oxidative modification of low-density
lipoprotein (LDL). The drugs digitoxin, derived from Digitalis lanata or
Digitalis purpurea, and digoxin derived from D lanata alone, have been
used in treatment of congestive heart failure. Rauwolfia serpentina root is
12 S. I. ABD RAZAK ET AL.

the natural source of alkaloid reserpine, which has been used to reduce
hypertension to minimize cardiac arrest (40).
Saffron was reported to be cardioprotective in isoproterenol-induced
myocardial damage. A study suggest that saffron at all doses was cardiopro-
tective by preserving hemodynamics and left ventricular functions, maintain-
ing structural integrity and augmenting antioxidant status. Antioxidants in
saffron tea (lycopene, a flavonoid) can reduce the risk of cardiovascular
diseases (49). In vitro study demonstrated the electrical conductivity effect
of saffron, which has a depressant effect on AV nodal rate-dependent proper-
ties. In high doses, saffron slowed the electrical conduction velocity in both
atrium and ventricle and may help in preventing arrhythmia. It was sug-
gested that crocetin and crocin activate different mechanisms in the vaso-
constriction pathway in hypertension, treating endothelial dysfunction,
especially aortic contraction problems, which is also known as having hypo-
tensive effect (25). Saffron is hypolipidemic and can reduce serum triglycer-
ide, total cholesterol, low-density lipoprotein (LDL) cholesterol, and very-
low-density lipoprotein (VLDLV) cholesterol levels in a daily dose of 25–100
mg.kg–1 by inhibiting pancreatic lipase, leading to the malabsorption of fat
and cholesterol and enhanced reduction of CVD risk such as in atherosclero-
sis, hypertriglyceridemia, and hypercholesterolemia (54).

Erectile dysfunction
According to the U.S. National Institutes of Health, erectile dysfunction (ED)
is defined as the inability to attain or maintain an erection sufficient for
satisfactory sexual performance. In other words, ED can be considered the
consistent or recurrent inability of a man to attain and/or maintain penile
erection sufficient for sexual activity. There are several ways of diagnosing
ED. The International Index of Erectile Function (IIEF) has been proposed as
a new standard method that has been widely used to asses ED using a
multidimensional scale that is more specific and sensitive for detecting
changes in erectile function (EF). Nitric oxide (NO) has been recognized as
a key mediator of penile erection and plays an important role in signaling
smooth muscle relaxation. Now, ED is regarded as a major health problem
that may rise to 322 million cases by the year 2025 (15).
There are several factors that lead to ED, including age, diabetes, cardio-
vascular disease, obesity, hypertension, hyperlipidemia, metabolic syndrome,
depression, lower urinary tract symptoms, smoking, penile fracture,
Peyronie’s disease, and side effects from other drugs (15, 52). The use of
several drugs can also cause erectile dysfunction: (1) antidepressants; imipra-
mine, doxepin, isocarboxazid, protryptiline, maprotiline, amitripline, amox-
apine; (2) antipsychotics; chlorpromazine, pimozide, thiotixene, sulpiride,
haloperidol; (3) anthypertensives; hydrochlorothiazide, reserpine, labetol,
 JOURNAL OF HERBS, SPICES & MEDICINAL PLANTS 13

atenolol, guanadrel, guanethidine, reserpine; (4) drug abuse; alcohol, cocaine,

amphetamines, MDMA; (5) anticonvulsants; barbiturates, phenytoin, primi-
done, carbamazepine; (6) other miscellaneous; ketamine, methadone, cime-
tidine, lithium, disulfiram, ketoconazole (15).
The treatment for ED begins with psychosexual and couples therapy for
purely psychogenic ED and relationship problems, followed by lifestyle
modification such as weight reduction, physical exercise, and smoking cessa-
tion, ending with testosterone supplement for associated hypogonadism.
Other approaches include first line (oral medication), second line (intraca-
vernosal and intrauretharal injection, vacuum constrictive devises, gene ther-
apy, growth factor targets, and combination therapy), and lastly (tissue
engineering, regenerative treatment, cavernous muscle cell auto transplanta-
tion, neural auto transplantation, penile cartilage rods, penile prosthe-
sis) (52).
Phosphodiesterase type 5 inhibitors (PDE5-Is) such as sildenafil, vardena-
fil, tadalafil, udenafil, and mirodenafil are structurally similar to cGMP and
will compete for the catalytic site of phosphodiesterase type 5 (PDE5), which
will slow down formation of 5′-guanosine monophosphate (GMP) from
cGMP. This action leads to accumulation of cGMP in smooth muscle cells,
causing relaxation outcome, increased arterial blood flow, and penile tumes-
cence. Studies suggest the use of a combination of L-arginine glutamate and
yohimbine hydrochloride will effectively improve EF in mild to moderate ED
through evaluation of IIEF score and diary logs of sexual intercourse success
rate. Other drugs that can be used in treating ED include dopamine receptor
agonists, prostaglandin E1(PGE1) known as alprostadil, nitric oxide synthase
(NOS) isoforms, papaverine, phentolamine, statin, L-citrulline, and pheny-
lephrine (15, 43).
The synthetic drugs may cause negative side effects such as muscle pain,
headache, blurred vision, dangerous interaction with other medication, and
also do not increase libido. Aphrodisiacs were used a thousand years ago in
Chinese, Egyptian, Greek, and Indian cultures which allowed human pro-
creation, increased sexually fulfilling relationships, and fertility.
Physiologically, these drugs enhance erection through hormonal changes,
increased blood flow, and relaxation of corpus cavernosum smooth muscle
tissue. Historically, aphrodisiacs are derived from Bufo toad, Tribulus terres-
tris, horny goat weed, MACA root, Panax ginseng, nutmeg, saffron, cacao,
and ambrein (41).
Studies have shown that saffron has significant effect on men with ED by
IIEF test and nocturnal penile tumescence (NPT), which is cheaper com-
pared to PDE5-Is. The component of saffron that gives this therapeutic affect
is crocin, especially at doses of 160 and 320 mg.kg–1 body weight, which
increased mounting frequency (MF), intromission frequency (IF), and erec-
tion frequency (EF) and reduced ejaculation latency (EL), intromission
14 S. I. ABD RAZAK ET AL.

latency (IL), and mount latency (ML). Although some studies showed ben-
eficial effects of saffron on sexual dysfunction, long-term outcomes have not
been documented (43).

Antidepressant
Depression is one of the most commonly diagnosed psychological disorders
or mental illnesses, and reports have showed that one out of five adults may
experience depression symptoms once in their lifetime. Depression was often
considered a sign of weakness rather than a health problem that might need
medical attention (8).
In the elderly, ageing-related and disease-related processes, including
arteriosclerosis and inflammatory, endocrine, and immune changes, com-
promise the integrity of frontostriatal pathways, the amygdala, and the
hippocampus, and increase vulnerability to depression. Childhood trauma
has a strong link to depression due to deficits in general emotion regula-
tion. Several treatments have been used to treat this disease, including
meditation or mindfulness, a process that leads to a mental state char-
acterized by nonjudgmental and nonreactive cognition and bodily sensa-
tion as well as external stimuli (5). Drugs have been used to relieve
depression, such as neural cell adhesion molecule (NCAM) protein, cita-
lopram HBr, and escitalopram, while other treatments may exist, for
example, repetitive transcranial magnetic stimulation (rTMS) antidepres-
sant treatment. Synthetic antidepressants may have side effects on the
patient such as dry mouth, constipation, and sexual dysfunction, thus
herbal drugs are a better alternative as they are safer, more tolerable,
and more accepted by patients (37).
Saffron has been shown to increase oxidative stress level and decrease
antioxidant defenses due to the lowering of antioxidant enzymes such as
SOD, catalase (CAT), and glutathione peroxidise, as well as increasing
markers of oxidative stress such as malondialdehyde (MDA) that cause
depression (4). Safranal and crocin increased the CAT activity in liver tissue,
and all three active components of saffron increased the SOD level and
glutathione availability (28).
Depression may depend on the serotoninergic effects. The chemical prop-
erties of neurotransmitters such as dopamine, norepinephrine, and serotonin
play important roles in depression. Crocin has shown antidepressant impact.
A nonselective serotonin (5-HT) receptor, chlorophenylpiperazine, displayed
affinity for the 5-HT2c family receptors, and research showed that crocin
influenced the serotonergic mechanisms by having an antagonistic action on
that receptor site and thus the serotonin uptake increased (31). Also, the
effects of saffron on serotonin availability can decrease and lower premenstr-
ual symptoms.
 JOURNAL OF HERBS, SPICES & MEDICINAL PLANTS 15

Antibacterial effect
Saffron has immunological function in human health by enhancing
immune response against bacterially caused infection or disease.
Carotenoids present in saffron increase natural killer cell (NK-cell) activ-
ity, increase lymphocyte response to mitogens, protect immune cells from
their own bactericidal production of reactive species, and increase total
white blood cells in HIV patients. Safranal and crocin were responsible for
bactericidal effect in food contamination caused by Salmonella (48).
Saffron petal was a effective antimicrobial in clothing and textile materials
as a natural dye against Staphylococcus aureus, Escherichia coli, and
Pseudomonas aeruginosa (22). The antibacterial action of different parts
of the saffron plant such as stigma and callus both showed varying degrees
of inhibitory effects on pathogenic bacterial strains. For example, saffron
stigma extract was more effective in inhibiting Sigella flexneri at lowest
concentration, 400 µg.mL–1 compared to saffron callus, 750 µg.mL–1 (45).
The ethyl acetate extract of various parts of saffron can be active against
bacteria (Microccucos luteus, Staphylococcus epidermitis, S. Aureus, and E.
coli) and fungi (Candida albicans, Aspergillus niger, and Cladospourium
sp.) (27).

Conclusion
This article reports the medical prospects of saffron, which has been exten-
sively explored by scientists. Prococrocin, crocin, and safranal are the most
influential bioactive components in saffron, which contribute to its health-
promotion and disease-preventing properties. The challenging part is sus-
taining its raw production to meet demands, which makes it an expensive
commodity in the market. Clinical trials are needed to ensure that there are
no adverse or side effects and to determine the correct dosage for human
consumption.

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